Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of calcium-activated, phospholipid-dependent protein kinase C by phorbol esters such as 12-O-tetradecanoyl-phorbol-13-acetate (TPA) has been shown to mediate release of hormones in many systems. To investigate the role of protein kinase C in the mechanism of pituitary ACTH release, we studied the effect of the following conditions on TPA mediated ACTH release in primary rat pituitary cultures; corticotropin releasing hormone (CRH), different concentrations of extracellular calcium (Ca+2), nifedipine (a calcium channel blocker), PGE2 and cortisol (regulators of ACTH secretions). TPA induced ACTH release in a dose dependent fashion with an ED50 of 4.2 x 10(-10) M. The maximal amount of ACTH release individually induced by TPA (10(-8) M) and CRH (10(-8)) were identical. TPA (10(-8)) potentiated the amount of ACTH release from cells already maximally stimulated with CRH (4 x 10(-8) M). TPA mediated ACTH release was dependent on extracellular calcium and inhibited by nifedipine, to a maximum of 35%. Cortisol decreased the amount of ACTH individually released by TPA and CRH in a similar and dose dependent fashion with maximal inhibition of 47% occurring at 10(-7) M. PGE2 caused a dose dependent reduction of TPA mediated ACTH release. In conclusion, the pathways of ACTH release induced by CRH and TPA are not entirely the same but may share a common regulatory pathway. Extracellular calcium and calcium cell influx may be important for maximal ACTH release induced by TPA. Protein kinase C activation may play an important role in CRH stimulated ACTH release.
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PMID:Characterization of 12-O-tetradecanoyl-phorbol-13 acetate mediated ACTH release. 284 20

Dispersed chick adrenocortical cells were incubated with mammalian and avian angiotensin-II, Ca2+, K+, verapamil, nifedipine, Ca2+ ionophore (A23187), protein kinase-C activator (phorbol 12-myristate 13-acetate; TPA), atrial natriuretic peptide (ANP), sodium nitroprusside (SNP) and ACTH. Secretion of aldosterone and corticosterone, and accumulation of cyclic nucleotides were assessed. Secretion of aldosterone was not affected by angiotensin-II, Ca2+ channel blockers, Ca2+ ionophore or TPA. ANP stimulated production of cyclic GMP (cGMP), and inhibited aldosterone secretion with a similar dose-response relationship. SNP also stimulated cGMP production and inhibited the ACTH-stimulated aldosterone secretion. The results indicate that ANP is an inhibitor of aldosterone secretion in birds and suggest that this inhibition is mediated by cGMP. In contrast to mammalian glomerulosa cells, angiotensin-II and the calcium-inositol phosphate-protein kinase C pathway appear not to be involved in the regulation of aldosterone secretion by avian adrenal cells.
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PMID:Regulation of aldosterone secretion by avian adrenocortical cells. 284 38

Protein kinase C is expressed in adrenal cortex as a single isoenzyme, whereas four isoforms are detected in brain tissue. Of the two major steroidogenic agents (ACTH and angiotensin II), only A II stimulates polyphosphoinositide hydrolysis and thus appears able to induce protein kinase C activation in adrenocortical cell. Although direct activation of the kinase partly mimics the steroidogenic effect of A II, no clear evidence has been obtained for a monodirectional effect of the kinase in the acute activation of adrenocortical cell steroidogenic activity. On the other hand, protein kinase C may play a key role in multidirectional regulatory events, resulting in the modulation of ACTH-responsive adenylate cyclase activity, in feed-back control or subtle transregulation (cross-talk) processes between different adrenocortical cell activation pathways triggered by different hormonal signals.
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PMID:[Protein kinase C and regulation of specialized steroidogenic functions of the adrenal cortical cell]. 284 65

Y-1 adrenal cells contain specific vasopressin (VP) binding sites (27,000 +/- 2,000 sites/cell) of high affinity (KD = 2.2 +/- 0.5 X 10(-9) M). VP which alone has no effect on cAMP production inhibited in a dose-dependent manner (ID50 = 3.5 +/- 0.7 X 10(-11) M) the ACTH-induced cAMP production by Y-1 cells. The inhibitory effect was completely blunted by a 24 h pretreatment of cells with 1 microgram/ml of pertussis toxin. Moreover, VP also stimulated in a dose-dependent manner (ED50 = 2.4 +/- 0.8 X 10(-9) M) the accumulation of inositol phosphates indicating that the VP receptors in Y-1 cells were of the V1 subtype. However, neither VP nor a phorbol ester (4 beta-phorbol 12-myristate 13-acetate, PMA) was able to stimulate Y-1 cell steroidogenesis. Since in a previous work we have shown that Y-1 cells contain high levels of protein kinase C, the present results indicate that the steroidogenic refractoriness of these cells to VP and PMA might involve some step beyond protein kinase C.
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PMID:Vasopressin induces breakdown of phosphoinositides in adrenal tumor Y-1 cells without a steroidogenic effect. 285 Feb 47

The cytoskeletons of Y-1 mouse adrenal tumor cells contain a calcium and phospholipid-dependent protein kinase (protein kinase C) that is bound sufficiently tight to resist extraction by 0.5% Triton but not by 1.0% Triton. The enzyme has been purified to near homogeneity from cytoskeleton and cytosol. It shows features typical of this type of kinase, namely a requirement for Ca2+ and phospholipid, stimulation by tumor promoters but not by nontumor-promoting phorbol esters, and inhibition by trifluoperazine. The enzyme shows specificity for four substrates found in the cytoskeleton, namely 80, 33, 20, and 18 kD. The first three substrates are phosphorylated by the enzyme; the fourth is dephosphorylated and is therefore affected by the kinase indirectly. The 80-kD protein is the kinase enzyme itself which is autophosphorylated in vitro and in the cytoskeleton. The 20-kD protein is myosin light chain. The 33- and 18-kD proteins are unidentified. The same substrates were phosphorylated when Y-1 cells were permeabilized with digitonin and incubated with [gamma-32P]ATP and phorbol-12-myristate-13-acetate. Partly purified protein kinase C changes the extent of phosphorylation of the same substrates when added to cytoskeletons previously extracted to remove endogenous protein kinase C. Addition of Ca2+, phosphatidylserine, and phorbol-12-myristate-13-acetate to cytoskeletons, and addition of these three agents plus protein kinase C to extracted cytoskeletons, causes these structures to undergo a rapid and extensive rounding. A similar change is induced in intact cells by addition of phorbol ester. It is concluded that protein kinase C is capable of changing the shape of adrenal cells by an action that involves autophosphorylation and phosphorylation of myosin light chain. This response may in turn be related to the steroidogenic responses to ACTH and cyclic AMP.
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PMID:Isolation and characterization of protein kinase C from Y-1 adrenal cell cytoskeleton. 291 25

Lithium stimulated corticotropin (ACTH) secretion by mouse pituitary tumor cells (AtT-20/D16-16) and by normal rat anterior pituitary cells in primary culture. Effects were observed at less than 2 mM LiCl. ACTH secretion was comparable in magnitude to that induced by other secretagogues, was calcium dependent, and was inhibited by somatostatin. Lithium also induced changes in [3H]inositide metabolism; these changes accompanied and were correlated with changes in ACTH secretion. The most prominent and reliable effect was to increase [3H]inositol monophosphate. Other secretagogues had no effect on [3H]inositides in the presence or absence of lithium. Pretreatment with lithium for 3 hr desensitized the cells to the effects of subsequent exposure to lithium. The cells were not desensitized to lithium by pretreatment with other secretagogues, nor were they desensitized by lithium to the effects of corticotropin-releasing factor, high potassium, or forskolin. However, pretreatment with lithium did desensitize the cells to stimulation by phorbol esters. The interaction between lithium and phorbol esters suggests the involvement of inositide metabolism and protein kinase C in the regulation of ACTH secretion and possibly of other hormones or neurotransmitters. It also suggests new avenues of research into the basis of lithium's psychopharmacological effects.
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PMID:Lithium induces corticotropin secretion and desensitization in cultured anterior pituitary cells. 298 36

Experiments were designed to evaluate the role of activators of protein kinase C, such as 1,2-diacylglycerol and phorbol esters, on the release of all the anterior pituitary (AP) hormones in vitro. Dispersed rat AP cells were incubated in the presence of 1,2-didecanoylglycerol (DiC10), a synthetic diacylglycerol, or phorbol 12,13-dibutyrate (PDBu), a tumor-promoting phorbol ester, at different concentrations and for varying periods of time. ACTH and beta-endorphin (beta-End) secretion were enhanced by DiC10 in a concentration-dependent manner, with a minimal effective concentration of 5 microM. PDBu at 5 nM produced a significant release of both ACTH and beta-End. The effect of DiC10 and PDBu was time dependent, with maximal responses occurring at 15-30 min for DiC10 and 30-60 min for PDBu. Release of GH was also enhanced significantly by DiC10 and PDBu, with minimal effective concentrations of 1 microM and 1 nM, respectively. Maximal release of GH was already attained within 15 min with DiC10 or 60 min with PDBu. In additional experiments, the effects of DiC10 and PDBu on secretion of LH, FSH, PRL, and TSH were evaluated. The results indicate that 5-25 microM DiC10 produced a concentration-dependent release of each of those hormones, and that 5 microM was the minimal effective concentration in every case. Nearly maximal stimulation was achieved within 15 min for each hormone. PDBu (50 nM) significantly enhanced LH, FSH, PRL, and TSH release within 30 min. Although qualitatively all hormones were similarly stimulated, both with respect to time and concentration, some quantitative differences were observed. ACTH and beta-End release were enhanced 100% by DiC10 and 300% by PDBu, whereas the increase in other hormones was of a lesser magnitude. The present study indicates that two specific stimulators of protein kinase C, diacylglycerol and phorbol ester, can enhance secretion of all AP hormones in a concentration- and time-dependent manner. This suggests that formation of endogenous 1,2-diacylglycerol may represent a physiological intracellular messenger in the events leading to AP peptide hormone release.
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PMID:1,2-Didecanoylglycerol and phorbol 12,13-dibutyrate enhance anterior pituitary hormone secretion in vitro. 299 14

The involvement of protein kinase C in normal corticotroph function was studied by analysis of the effects of the phorbol ester derivative phorbol 12-myristate-13-acetate (PMA) and the synthetic diacylglycerol dioctanoylglycerol (DOG) on basal and stimulated ACTH release in cultured rat anterior pituitary cells. Incubation of rat pituitary cells with increasing concentrations of PMA or DOG caused dose-related increases in ACTH release up to 13.4 +/- 2.1- and 10.1 +/- 0.9-fold, respectively, similar to that caused by CRF (9.8 +/- 1.6-fold). Also, stimulation of endogenous diglyceride formation by phospholipase C (100 mU/ml) stimulated ACTH release by 2.5 +/- 0.1-fold. In cells incubated with maximum stimulatory concentrations of CRF (10 nM) or 8-bromo-cAMP (8-Br-cAMP; 5 mM), addition of either 100 microM DOG or 100 nM PMA caused significantly higher ACTH responses than those obtained with CRF, 8-Br-cAMP, DOG, or PMA alone. 8-Br-cAMP (5 mM) and 10 nM CRF significantly increased the effect of 100 nM PMA by 1.4 +/- 0.2- and 1.5 +/- 0.1-fold, respectively. Combinations of 10 nM CRF with either vasopressin (VP) or angiotensin II (AII) increased ACTH secretion to values higher than those produced by CRF, VP, or AII alone. However, addition of maximal stimulatory concentrations of VP or AII (10 nM) did not further increase the effects of either PMA alone or PMA/CRF combinations, indicating that their mechanisms of action may be similar to that of PMA. These results indicate that in addition to the established cAMP-dependent mechanism, stimulation of ACTH release in normal pituitary cells may be elicited by activation of protein kinase C. The evidence also suggests that protein kinase C is involved during stimulation of ACTH release by the cAMP-independent regulators VP and AII and in the synergistic effects of VP and AII with CRF on the corticotroph.
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PMID:Involvement of protein kinase C in the regulation of adrenocorticotropin release from rat anterior pituitary cells. 300 Jul 34

Y-1 adrenal tumor cells and rat fasciculata cells were shown to possess an enzyme with the properties of protein kinase C. Activity was stimulated by Ca2+ and phospholipid (specifically phosphatidylserine). Enzyme activity was stimulated by addition of phorbol ester to a cell homogenate (ED50 10 nM) and inhibited by trifluoperazine (ID50 10 microM). ACTH and cyclic AMP added to Y-1 cells increased the activity of protein kinase C. Dose-response curves with ACTH showed that the hormone was effective in stimulating protein kinase C at lower concentrations than those required to increase steroid synthesis. When phorbol ester was added to Y-1 cells, total kinase C activity was diminished. Neither phorbol ester nor ACTH causes redistribution of protein kinase C between membranes and cytosol. Phorbol ester also stimulates steroid production by Y-1 cells. Protein kinase C phosphorylates 5 proteins in Y-1 cells (67, 61, 32, 16 and less than 14.4 kDa). Puromycin and cycloheximide increase the activity of protein kinase C in adrenal cells. It is concluded that protein kinase C may play an ancillary role in regulation of adrenal steroid synthesis but does not mediate the classical steroidogenic response that results from activation of adenylate cyclase by ACTH.
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PMID:Protein kinase C in adrenal cells: possible role in regulation of steroid synthesis. 300 Aug 51

The activity of the POMC gene is regulated by both stimulatory and inhibitory hormones. Presumably, some balance exists in the influence of these hormones in order to maintain a steady-state level of activity of this gene. Physiological insults, such as stress, may upset this balance and change the rate of production of POMC and its biologically active peptides. The relative strength of these different hormones may therefore determine the long-term expression of this gene. Chronic administration of CRF to rats, primates and humans produces prolonged increases in plasma ACTH levels. This long-term effect is most likely due to an activation of the POMC gene. Interestingly, chronic treatment of anterior pituitary cells with CRF desensitizes CRF receptors. Thus, despite the corticotrophs becoming refractory to the acute stimulatory actions of CRF, the POMC gene remains stimulated. These findings suggest that corticotrophs do not have to be continuously activated by CRF to maintain a long-term increase in POMC gene expression. This contrasts with the actions of glucocorticoids whose effects are abruptly terminated following their removal from the target tissue. The molecular basis of this form of cellular memory to the actions of CRF may involve cAMP regulatory phosphoproteins binding to and activating the POMC gene. If this phenomenon is shown to occur and the phosphorylation state of these nuclear proteins is found to govern their level of interaction with POMC gene, then it would represent a novel mechanism of gene regulation. Proof for this mechanism and the elucidation of how other second messengers such as protein kinase C and calcium regulate the POMC gene will greatly aid our understanding of the precise molecular mechanisms controlling opioid peptide expression.
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PMID:Hormone receptor regulated proopiomelanocortin gene expression. 302 24


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